Novel mechanisms of inflammatory signalling in cystic fibrosis
RCSI research illustrates how inflammatory signalling in cystic fibrosis can be mediated by an increase in extracellular vesicles.
Cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. This genetic disease is characterised by persistent airway infection that eventually leads to respiratory failure and early death.
Airways inflammation in CF occurs from an early age, manifesting before recognized clinical symptoms, and contributes significantly to disease progression and shortened life expectancy. In addition to impairment of epithelial ion transport, epithelial dysfunction has been implicated in chronic inflammation and infection of the CF airway. This leads to the migration of neutrophils from the blood into the airways early in the CF disease process.
Because of this, there is a need to identify novel factors that regulate neutrophilic inflammation in early CF disease as the targeting of these regulatory mechanisms may provide clinicians with an opportunity to delay disease progression early in the course of irreversible airway destruction.
In this study available here, the team led by Dr Judith Coppinger and Prof. Paul McNally at RCSI University of Medicine and Health Sciences and the National Children’s Research Centre (NCRC) Ireland have identified a novel mechanism of inflammatory cell communication in young children with CF. This research highlights extracellular vesicles (EVs) as novel communicators in CF which could open up new opportunities for treatment.
Small EVs are released from most living cells and enriched with protein cargo that enables communication with neighbouring cells. The ability of EVs to bear disease-specific and often inflammatory signatures has been increasingly recognised across several diseases.
The CF translational research programme team led Dr Coppinger and her team, alongside academic and clinical consultants from University College Dublin, Trinity College Dublin, University of Limerick and their affiliated hospitals, demonstrate how CF inflammatory cell function can be regulated by EVs released from lung epithelial cells with mutated CFTR.
The RCSI team began by confirming that EV release is upregulated in CF bronchial models and bronchoalveolar lavage fluid (BALF) from people with CF (PWCF) when compared with controls. Interestingly, the findings revealed that the number of EVs released increased with age. The team also illustrated how EV release could be modulated by CFTR correctors and potentiators such as Lumacaftor, Tezacaftor and Ivacaftor, drugs that are commonly used in clinical practice for PWCF.
In the next phase of the study, mass spectrometry analysis was employed to demonstrate how EVs isolated from CF bronchial cells and BALF from PWCF are enriched with proteins that are involved in leucocyte recruitment and activation.
This finding supports the theory that an intrinsic inflammatory state may exist in CF lungs even in the absence of infection. Additionally, there were unique protein fingerprints in EVs isolated from the BALF of PWCF of different ages, even in young children, again indicating possible intrinsic inflammation at an early age, as well as a role for EVs as biomarkers for EVs in CF.
Finally, the Coppinger Lab demonstrated EVs were able to bind and activate neutrophils from donors, stimulating neutrophil degranulation and induced chemotaxis. EVs were also revealed to be capable of stimulating the RAGE receptor and its downstream pathways in neutrophils.
RAGE is known to mediate neutrophil adhesion to and subsequent migration across intestinal epithelial monolayers. When S100 A12 described above is a ligand for RAGE and this is silenced in EVs from bronchial epithelial cells, a significant decrease in neutrophil migration was observed, revealing altering EV content to modulate neutrophil activities as a potential avenue for new anti-inflammatory responses in CF.
In this translational study, the research team highlighted a potential relationship between reduced CFTR activity and inflammation in the setting of CF. Through the study of EVs, the researchers furthered our understanding of disease mechanisms in CF by providing novel insights into epithelial-neutrophil communication. Therapeutic strategies that target EVs or the proteins derived from them could potentially result in improved clinical outcomes for patients with CF in the future.
Journal Article Information:
Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis
Thorax 2020, 75 (6), 449–458.
http://dx.doi.org/10.1136/thoraxjnl-2019-214027
